Erythropoietin (EPO) is one of the most attractive agents currently being studied to improve outcome from TBI. In experimental models, EPO has improved outcome after TBI, and many other central nervous system disorders. EPO has been shown to have neuroprotective effects when given early post-injury, and to have effects that enhance neurological recovery even when given at later times after injury. The neuroprotective mechanisms are probably complex, involving anti-inflammatory, anti-apoptotic, and vascular actions. The time window for EPO-induced neuroprotection is at least 6 hr post-injury. Despite these positive features observed in the laboratory, it has been difficult to translate EPO into the clinical setting for TBI because the doses of EPO required for neuroprotection and enhancement of neurological recovery have adverse effects in patients. Almost all studies of EPO in critically ill, trauma, and post-operative patients have shown an increased risk of thrombosis with EPO administration. The hematopoietic and tissue protective effects of EPO, however, can be separated. Araim Pharmaceuticals has developed a short, synthetic EPO-mimetic peptide (pyroglutamate Helix B surface peptide [pHBSP]) that retains EPO's neuroprotective activities, but not the hematopoietic activities responsible for the adverse effect of EPO. Preliminary data demonstrates in a TBI model that pHBSP improves neurological recovery similar to EPO. The goal of this project is to perform the preclinical work necessary to move pHBSP from the laboratory to a phase II clinical trial by the end of the grant period. Araim Pharmaceuticals (Ossining, NY) has already completed phase I safety/toxicity studies in humans. The specific aims to accomplish the preclinical work in TBI include the following: 1-To determine the optimal dose level, effective time window, and optimal dose regimen for acute dosing of pHBSP for treatment of TBI, 2-To confirm efficacy of optimal dosing regimen of pHBSP in a spectrum of injury severities, 3-To confirm efficacy of optimal dosing regimen of pHBSP in a second TBI injury model, 4-To study gender and age differences in response to optimal dosing regimen of pHBSP, 5-To submit an IND application for phase II clinical trial.